The absence of safe, effective strategies for the management of ocular pain is motivating the development of a novel topical drug suitable for patient self-administration. Conventional local anesthetics, such as proparacaine, inhibit voltage-gated Na+ ion channels and are highly effective for the management of ocular pain in acute, in-office settings. However, these agents are short acting and toxic to the corneal surface, which prevents their use beyond a few administrations. The guanidinium toxins are a collection of naturally-occurring small molecules that inhibit six of the nine isoforms of the mammalian voltage-gated sodium channel (NaV1.1- 1.4, 1.6, 1.7) at low nanomolar concentrations. In animal models of corneal tactile sensitivity, topical administration of these agents has been shown to produce profound anesthesia with a duration of action that greatly exceeds that of proparacaine. In addition, these compounds appear to cause little to no toxicity to the corneal surface. A significant liability of the natural compounds is poor permeability through the corneal epithelium, which leads to high dosing requirements. SiteOne has technology in place to prepare analogues of the natural guanidinium toxins by de novo chemical synthesis. Using this technology, we have generated a collection of ~200 novel guanidinium toxin derivatives with range of structural features and physicochemical properties. By leveraging our collection of compounds and the ability to prepare novel, optimized derivatives, we aim to identify new chemical entities with improved pharmaceutical properties for the treatment of ocular pain.